Definition, Etiology, PathogenesisTop
Adult-onset Still disease (AOSD) is a disease occurring in persons aged >16 years and resembling a systemic form of juvenile idiopathic arthritis. It may be associated with fever, rash, lymphadenopathy, splenomegaly, serositis, and inflammation of multiple organs. The condition was first described in 1971 in a case series of adult patients with symptoms reminiscent of children with Still disease (now known as systemic juvenile idiopathic arthritis). It is classically characterized by spiking fevers, arthritis, and an evanescent salmon-colored rash. AOSD is a rare condition, with incidence rates ranging from 0.16 to 0.4/100,000 patient-years. The condition typically affects young adults, with a median age of onset of 36 years, and predominantly women. The exact etiology of AOSD is still unknown. It has been associated with several different human leukocyte antigens (HLAs), including HLA-Bw35, HLA-DR4, and HLA-DrW6; however, the strengths of these associations remain unclear. It is also proposed that a preceding infection may play a role in the etiology of AOSD, leading to an epigenetic effect. Different inflammatory mediators, including interleukin 1 (IL-1), IL-6, IL-18, and tumor necrosis factor (TNF)-alpha, likely play a role in the mechanism of the disease and may be targeted by therapeutic interventions.
Clinical Features and Natural HistoryTop
AOSD develops after the age of 16. In adults the symptoms may be due to the first occurrence of the disease or a relapse. The course of AOSD may be self-limiting (lasting <1 year), relapsing (relapses may be very frequent), or chronic (symptoms are continuously present throughout the year). In some patients significant joint destruction occurs.
Symptoms (Table 18.1-1):
1) Most frequent:
a) Fever (>80% of cases; usually >39 degrees Celsius, most commonly in the evening or twice during a 24-hour period).
b) Sore throat with features of inflammation (>50%; frequently develops several days or weeks prior to other symptoms).
c) Salmon-pink macular or maculopapular rash (>80%; often transient, develops only during episodes of fever, rarely pruritic, most frequently located on the trunk and proximal limbs, less often on the face; it may be triggered by heat [eg, following a hot bath] or skin abrasion [eg, scratchy clothing]).
d) Arthralgia (>90%; worsens during febrile periods; occasionally arthritis, most commonly affecting the knees and wrists; approximately one-fourth of patients develop ankyloses of the involved joints).
e) Myalgia (>80%).
f) Lymphadenopathy (>50%; most frequently affecting the cervical lymph nodes; the lymph nodes may be tender; retroperitoneal lymphadenopathy may cause abdominal pain that is difficult to diagnose).
g) Splenomegaly, hepatomegaly (50%).
2) Less frequent: Symptoms of pleuritis or pericarditis, weight loss.
3) Rare: Pulmonary fibrosis, myocarditis or cardiac tamponade, hair loss, Sjögren syndrome, macrophage activation syndrome (MAS) (a form of hemophagocytic lymphohistiocytosis [HLH]), aseptic meningitis, peripheral neuropathy, amyloidosis, subacute glomerulonephritis and interstitial nephritis, hemolytic anemia, disseminated intravascular coagulation, cataract, hearing impairment.
1. Laboratory tests: In periods of increased disease activity the following features are observed:
1) Elevated erythrocyte sedimentation rate (ESR) and plasma C-reactive protein (CRP) levels.
2) Leukocytosis (often >20×109/L) with >80% of neutrophils in the differential counts.
6) Very high serum ferritin levels (levels >3000 ng/mL are suggestive of AOSD [in adults, this is the second most frequent cause of ferritin levels >1000 ng/mL next to hemophagocytic syndrome: see Hemophagocytic Lymphohistiocytosis]; the increase correlates with the disease activity). Glycosylated ferritin <20% adds to diagnostic accuracy.
7) Elevated serum aminotransferase and lactate dehydrogenase (LDH) levels.
8) IgM rheumatoid factor (RF) and antinuclear antibodies (ANAs) (observed in <10% of patients; in diagnostic workup negative RF and ANAs are suggestive of Still disease). IL-18 levels are elevated.
2. Synovial fluid: Synovial aspirate in AOSD is nonspecific, and features are consistent with inflammatory arthritis.
3. Imaging studies: Radiographs of the hands are usually nonspecific and not very helpful in establishing the diagnosis of AOSD. Radiographs of the involved joints may reveal periarticular osteopenia, narrowing of the joint space, erosions, as well as early development of ankylosis. In some patients, rapid destruction of 1 or both hip joints, less often of a knee joint, is observed. Computed tomography (CT) may demonstrate retroperitoneal lymphadenopathy.
The key categories of conditions in the differential diagnosis for AOSD are infections, malignancies, and autoimmune diseases. Potential infections to rule out include HIV, cytomegalovirus, Epstein-Barr virus, hepatitis B, hepatitis C, parvovirus B19, rubella, infective endocarditis, syphilis, and toxoplasmosis. Malignancies to exclude are primarily malignant lymphomas or any other metastatic disease. Potential autoimmune diseases, which may mimic AOSD, include systemic lupus erythematous, rheumatoid arthritis, systemic vasculitis, familial Mediterranean fever, hemophagocytic syndrome, Sweet or Schnitzler syndrome, Kikuchi or Fujimoto disease, and sarcoidosis.
Testing Prior to Treatment Initiation: Prior to initiation of any therapy, a complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, serum creatinine levels, and liver profile should be ordered. The treatment options provided below are listed in the order of management for increasing severity of disease. Expert consultation is recommended for guidance regarding treatment decision-making.
1. Nonsteroidal anti-inflammatory drugs (NSAIDs): Retrospective cohort studies have shown NSAIDs to be ineffective in controlling symptoms of AOSD, with >80% of patients failing to respond. In addition, up to 20% of patients experienced an adverse event. Therefore, NSAIDs are not an effective agent in controlling disease activity. They may be used as adjunctive therapy for arthritic symptoms, but high-quality evidence for their use in this role is lacking. NSAIDs could be tried alone in a mild form of the disease for a limited period of time.
2. Glucocorticoids: Retrospective cohort studies have shown that glucocorticoids at an oral dose of 0.5 to 1 mg/kg daily of prednisone (or an equivalent dose of methylprednisolone) may be used, as they were effective in controlling AOSD symptoms in up to 65% of patients.Evidence 1Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational and retrospective character of the study. Fautrel B, Borget C, Rozenberg S, et al. Corticosteroid sparing effect of low dose methotrexate treatment in adult Still's disease. J Rheumatol. 1999 Feb;26(2):373-8. PubMed PMID: 9972972. Clinical improvement may be evident within hours of initiating therapy. Tapering usually begins within 4 to 6 weeks after initiating treatment. However, a large proportion of patients (40%-45%) become steroid-dependent and unable to completely taper off prednisone, which subjects them to many potential adverse effects, such as glucocorticoid-induced osteoporosis and avascular necrosis, among many others.
3. Disease-modifying antirheumatic drugs (DMARDs): Adding a DMARD is critical, given the high percentage of patients who become steroid-dependent. Methotrexate is the drug suggested when selecting a steroid-sparing agent. Doses of oral methotrexate range from 7.5 mg/wk to 25 mg/wk. Although methotrexate is the most studied DMARD in the treatment of AOSD, the evidence for its use is still lacking, coming only from small retrospective cohorts. These small studies have shown that addition of methotrexate may achieve a partial or complete remission of AOSD and allows at least a majority of patients to either reduce their glucocorticoid dose, or to taper it off completely.Evidence 2Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational and retrospective character of the study. Fautrel B, Borget C, Rozenberg S, et al. Corticosteroid sparing effect of low dose methotrexate treatment in adult Still's disease. J Rheumatol. 1999 Feb;26(2):373-8. PubMed PMID: 9972972. Methotrexate has been shown to have similar efficacy in patients with AOSD and primarily systemic or articular manifestations. Patients initiating conventional synthetic DMARDs should have hepatitis virus screening performed prior to initiation.
4. Interleukin-1 (IL-1) antagonists: Three available IL-1 inhibitors—anakinra, canakinumab, rilonacept—have been tried in patients with AOSD. A systematic review performed in 2021 investigated the efficacy and safety of IL-1 inhibitors in AOSD, with anakinra and canakinumab recommended as treatments in patients with AOSD refractory to glucocorticoids.Evidence 3Kedor C, Tomaras S, Baeumer D, Feist E. Update on the therapy of adult-onset Still's disease with a focus on IL-1-inhibition: a systematic review. Ther Adv Musculoskelet Dis. 2021 Nov 24;13:1759720X211059598. doi: 10.1177/1759720X211059598. PMID: 34868356; PMCID: PMC8641116. Castañeda S, Atienza-Mateo B, Martín-Varillas JL, Serra López-Matencio JM, González-Gay MA. Anakinra for the treatment of adult-onset Still's disease. Expert Rev Clin Immunol. 2018 Dec;14(12):979-992. doi: 10.1080/1744666X.2018.1536548. Epub 2018 Oct 22. PMID: 30324816. Gao X, Petryna O. Clinical Utility of MBDA Panel in the Management of Adult Onset Still's Disease. Mediterr J Rheumatol. 2017 Sep 29;28(3):157-160. doi: 10.31138/mjr.28.3.157. PMID: 32185275; PMCID: PMC7046059.
1) Anakinra is a human IL-1 receptor antagonist given as a daily subcutaneous injection that might be considered in those resistant to the therapies described above. It is the most frequently used anti-IL-1 agent in patients with AOSD. A systematic review performed in 2018 summarized the available evidence on anakinra.
A small open randomized trial assessed the efficacy of anakinra as a steroid-sparing agent in patients with AOSD with active disease despite treatment with prednisolone ≥10 mg per day, with or without concomitant DMARD use. Additionally, there are multiple retrospective studies, case series, and >80 case reports identifying the role of anakinra in AOSD.
In 2018 the European Medicines Agency (EMA) approved the extension of anakinra to encompass the treatment of Still disease (both systemic juvenile idiopathic arthritis and AOSD) in all 28 European Union member states. The initial dose in adults is 100 mg per day administered subcutaneously.
2) Canakinumab is a fully humanized monoclonal antibody against IL-1. Unlike anakinra, canakinumab has a much longer half-life (26 days vs 6 hours). Nine papers have been published to date (2016-2021) on canakinumab used as treatment for patients with AOSD, involving a total of 110 patients. It is also approved by the EMA for the treatment of patients with AOSD. Its cost for many is prohibitively high.
3) Rilonacept is a dimeric fusion protein that neutralizes IL-1. It is administered once a week. The evidence for this drug is limited to 2 case reports of patients with AOSD refractory to prednisone, methotrexate, and anakinra, but responding to rilonacept. It is currently not licensed for use in AOSD in the United States or Europe.
5. TNF-alpha inhibitors: Three available TNF-alpha inhibitors—infliximab, etanercept, and adalimumab—have been tried in patients with AOSD.
1) Infliximab is a chimeric monoclonal antibody against TNF-alpha. There are a number of small case series in which treatment with infliximab improved systemic and articular symptoms of AOSD, while also improving inflammatory markers (ESR, CRP) and ferritin levels. There are also case series suggesting infliximab may be used as a steroid-sparing agent in patients treated with prednisone and methotrexate. However, the evidence for infliximab in AOSD is limited to small retrospective case series and 1 prospective open-label trial consisting of only 4 patients.
2) Adalimumab is a fully human monoclonal antibody against TNF-alpha. Case reports and case series suggest that adalimumab may be effective in patients with AOSD and can be used as a steroid-sparing agent. The quality of evidence regarding the role of adalimumab role in the treatment of AOSD is limited to case reports and case series.
3) Etanercept is a recombinant molecule of fragments of soluble TNF-alpha receptor linked to the Fc portion of human IgG. A small prospective cohort study of 12 patients with AOSD with severe arthritic symptoms refractory to DMARDs who were treated with etanercept suggested a modest improvement in the arthritic symptoms, but most patients did not have a complete response. A number of other case reports and case series have reported that etanercept was able to achieve a partial response in patients with AOSD and primary chronic arthritic symptoms, but few were able to achieve disease remission. Like with the other TNF-alpha inhibitors, the quality of evidence for the role of etanercept role in the treatment of AOSD is poor, limited primarily to case reports, case series, and 1 small prospective open-label study. TNF-alpha inhibitors might be considered in those who do not respond to a more standard treatment with glucocorticoids and methotrexate.
6. Interleukin-6 (IL-6) antagonist: Tocilizumab is a fully humanized monoclonal antibody against IL-6 receptors, which was used in 1 prospective open-label trial of 14 patients with AOSD (who previously failed anakinra and at least 1 TNF-alpha inhibitor). After 6 months of therapy with tocilizumab, 57% of patients had remission of joint symptoms and 86% had resolution of the systemic symptoms. Another retrospective review consisted of 16 patients with AOSD treated previously with at least 1 biologic before switching to tocilizumab.Evidence 4Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data. Ortiz-Sanjuán F, Blanco R, Calvo-Rio V, et al. Efficacy of tocilizumab in conventional treatment-refractory adult-onset Still's disease: multicenter retrospective open-label study of thirty-four patients. Arthritis Rheumatol. 2014 Jun;66(6):1659-65. doi: 10.1002/art.38398. PubMed PMID: 24515813. All but one patient responded well after treatment with tocilizumab, and 2 patients were able to completely withdraw their glucocorticoid therapy. The effects were quite rapid, with a normalization of CRP levels by 7.1 weeks (mean), and ferritin levels by 5.8 weeks (mean). Overall, tocilizumab remains a promising option for patients with refractory AOSD with both systemic and articular manifestations. However, the quality of evidence is limited to case reports, case series, and 1 prospective open-label cohort study. As such, tocilizumab may be considered in patients failing therapy with glucocorticoids and methotrexate. Patients receiving IL-6 inhibition should have lipid levels monitored.
7. Janus kinase (JAK) inhibitors: There is limited evidence from case series on the use of JAK inhibitors in patients with AOSD refractory to conventional therapies.Evidence 5Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data involving a small number of patients. Hu Q, Wang M, Jia J, Teng J, et al. Tofacitinib in refractory adult-onset Still's disease: 14 cases from a single centre in China. Ann Rheum Dis. 2020 Jun;79(6):842-844. doi: 10.1136/annrheumdis-2019-216699. Epub 2020 Feb 20. PMID: 32079571; PMCID: PMC7286046. Patients should have lipid levels monitored and hepatitis and latent tuberculosis screening if JAK inhibitors are chosen.
8. IV immunoglobulins: Limited evidence from case reports and case series supports some benefit of IV immunoglobulins infusions in patients resistant to or unable to tolerate other forms of therapy.Evidence 6Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data involving a small number of patients. Vignes S, Wechsler B, Amoura Z, et al. Intravenous immunoglobulin in adult Still's disease refractory to non-steroidal anti-inflammatory drugs. Clin Exp Rheumatol. 1998 May-Jun;16(3):295-8. PubMed PMID: 9631752.
9. The use of an IL-18-binding protein and IL-6 antagonist sarilumab has been described in the literature in refractory cases.
The natural history of AOSD can be quite variable. Some patients have a single systemic self-limited episode with symptoms improving within a few months and resolving by 1 year. Other patients have a polycyclic form of the disease, with multiple flares of the systemic and arthritic symptoms and clear periods of remission between the flares. Finally, the remaining patients have a form associated with chronic disease, where inflammatory arthritis is the predominant manifestation. These patients are prone to develop secondary osteoarthritis, with associated impact on health-related quality of life and disability.
Polyarthritis and arthritis affecting the large joints (shoulder, hip) at the onset of the disease are associated with an increased risk of developing chronic disease. AA amyloidosis is a rare complication of AOSD (<1%), which is attributed to chronic uncontrolled systemic inflammation. The incidence of AA amyloidosis is low, especially with appropriate therapies to decrease the level of inflammation. Death may occur due to infection, liver failure, amyloidosis, respiratory failure, heart failure, or disseminated intravascular coagulation.
1) Fever ≥39°C persisting for ≥1 week
2) Arthralgia/arthritis persisting for ≥2 weeks
3) Typical rash
4) White blood cell count ≥10×109/L (>80% neutrophils)
1) Sore throat
2) Lymphadenopathy and/or splenomegaly
3) Increased serum aminotransferase or lactate dehydrogenase levels (after other causes have been excluded)
4) Negative IgM rheumatoid factor and antinuclear antibodies (immunofluorescence assay)
1) Infections, in particular sepsis and infectious mononucleosis
2) Malignancy, in particular lymphoma
3) Other rheumatic diseases, in particular polyarteritis nodosa and vasculitis in the course of rheumatoid arthritis
For the diagnosis of adult-onset Still disease, ≥5 criteria must be met, including ≥2 major. In patients with any of the exclusion criteria, the diagnosis is excluded.
Sensitivity of the criteria is 80.6%, and specificity is 98.5%.
Source: J Rheumatol. 1992;19(3):424-30.
|Notes: An alternative diagnostic score by Fautrel, without exclusion criteria, is available at www.journals.lww.com. According to this scale, ≥4 major criteria must be met for adult-onset Still disease to be considered (spiking fever of ≥39 degrees Celsius, arthralgia, transient erythema, pharyngitis, polymorphonuclear neutrophil count of ≥80%, glycosylated ferritin of <20%); or 3 major and 2 minor criteria (maculopapular rash and white blood cell count of ≥10×109/L).|